INTRODUCTION:

The prevalence of hypertension continues to increase. It is estimated that by 2025, there will be 1.5 billion people with hypertension worldwide¹.

Hypertension is a medical condition in which arterial blood pressure is above normal in the long term. Approximately 90–95% of cases are primary hypertension, which is caused by an unhealthy lifestyle and non-specific genetic factors². Hypertension is the dominant risk factor for cardiovascular disease^3,4. In addition, hypertension is also a risk factor for chronic kidney disease and stroke⁵.

Blood pressure that is well controlled can reduce the risk of cardiovascular events and can also reduce morbidity and mortality in hypertensivepatients^6,7,8,9. The commonly recommended way to achieve controlled blood pressure is the adoption of a good lifestyle and diet, accompanied by an adequate intensity of drug therapy¹⁰. Drug efficacy is influenced by a combination of several intrinsic and extrinsic factors. Genetics is an intrinsic factor that influences up to 95% of individual variability in responding to drugs^11,12. Genetic variation among human populations is often found in certain ethnicities butrarely or not found in other ethnicities. The results of a systematic review conducted by Brewster et al.¹³ in Europe showed that patients of African descent responded better to antihypertensive calcium channel blockers and diuretics, while the responses to beta-blockers and angiotensin-converting enzyme inhibitors (ACE inhibitors and ARBs) were very poor. Meanwhile, several studies involving South Asian ethnic groups showed that there was no strong evidence of differences in antihypertensive efficacy among these ethnic groups.Another study involving hypertensive primary care patients in England found that the general reduction in blood pressure with the new use of CCBs was similar to that with the new use of ACE inhibitors or ARBs in non-black individuals without diabetes.For blacks without diabetes, the new use of CCBs demonstrated a numerically greater reduction in blood pressure than ACE inhibitors or ARBs¹⁴.

The use of antihypertensive drugs based on ethnic groups has been described in several hypertension treatment guidelines. The hypertension treatment guide of JNC 8¹⁵recommends the use of ACE inhibitors, ARBs, calcium channel blockers, or thiazide-type diuretics as initial therapy in non-black persons with essential hypertension or hypertension with diabetes, whereas in black individuals with hypertension, including those with diabetes, it is not recommended. using an ACE inhibitor or ARBs as initial therapy.The NICE Guideline (2019)¹⁶states that adults of black African or African-Caribbean ethnicity who have just been diagnosed with hypertension are not advised to use ACE inhibitors or ARBs in the first-line treatment for hypertension. From the explanations above, it can be seen that individuals with hypertension from different ethnic groups are recommended to use different antihypertensive drugs.

Indonesia has great ethnic diversity. However, Indonesia does not have data regarding the type of antihypertensive that is most effective for hypertension patients based on ethnic origin¹⁷. Tolaki and Muna are two of the four indigenous ethnicities of Southeast Sulawesi Province, Indonesia. These two ethnicities have the largest population compared to other indigenous ethnicities. The Tolaki ethnic group inhabits the Southeast Sulawesi peninsula, while the Muna ethnic group generally inhabits a separate island in the southern part of Southeast Sulawesi. These two ethnicities have different languages, customs, cultures, and even different physical characteristics. The Muna ethnicity has similarities with the Polynesian and Melanesian races in the Pacific and Australia, i.e., straight stature, tanned dark skin and tend to be black, wide nose and forehead, and wavy curly hair¹⁸. Meanwhile, the physical characteristics of the Tolaki ethnicity are yellowish-white skin, slanted eyes, and straight hair¹⁹. The striking physical differences between the Tolaki and Muna ethnicities have led to suspicions that the two ethnicities have different genetic variations, which in turn will affect the body's response to drugs, including antihypertensive ARBs. However, research related to this matter has not received the attention of many researchers.

The effectiveness of ARBs and ACE inhibitors as first-line treatments for hypertension has been widely studied and published.Other studies have shown that ARBs and ACE inhibitors are equally effective in reducing hypertension. However, ARBs provide a better safety profile, namely a lower risk of angioedema, pancreatitis, and gastrointestinal bleeding.In addition, ARBs significantly do not cause the dry cough that often occurs with ACE inhibitors. Some researchers suggest further research on ARBs to see the potential for heterogeneity between individuals^20,^21,22,23.

Candesartan therapy for 4 and 8 weeks significantly reduced branchial blood pressure and central blood pressure²⁴. In the 2017 Indonesian National Formulary²⁵, candesartan is one of the ARBs included in the list of drugs used in hypertension therapy. Candesartan is a highly selective, long-acting compound that does not interact with food and has high antihypertensivepotency²⁶. Candesartan is administered orally as the ester prodrug candesartan cilexetil, which is rapidly and completely hydrolyzed to the active candesartan compound^27,28. Candesartan lowers blood pressure by binding to angiotensin II type 1 (AT1) receptors in various tissues so that angiotensin II cannot bind to AT1^29,30,31. However, studies and publications on the efficacy of candesartan cilexetil in Tolaki and Muna ethnic populations with hypertension have not received much attention. Therefore, this study aims to determine the efficacy and tolerability of candesartan cilexetil monotherapy in Tolaki and Muna ethnicities with hypertension.

RESEARCH METHODS:

This research is a non-experimental study with a retrospective cohort research design.The researchdata was taken from the medical records of hypertensive patients who underwent health checksat the internal medicine polyclinic at the outpatient installation at two hospitals in Kendari City (Indonesia)in the periodJanuary 2016 to December 2021. The inclusion criteria in this study were patients with primary hypertension or hypertension with type 2 diabetes mellitus, Muna or Tolaki ethnicity, aged over 18 years, and having blood pressure records at the time of diagnosis of hypertension and one month after undergoingcandesartancilexetil monotherapy (8 mg once daily). The research protocol has received ethical approval from the research ethics commission at the local university.

Evaluation of the efficacy of candesartan cilexetil 8 mg monotherapy for one month in two ethnic groups includes the prevalence of patients who achieved the therapy target according to JNC 8, as well as the average value of reduction in systolic, diastolic, and mean arterial pressure (MAP). Blood pressure values that indicate successful therapy are guided by the Joint National Committee 8 hypertension therapy guidelines (2014). In patients aged < 60 years, systolic blood pressure is< 140 mmHg and diastolic blood pressure is< 90 mmHg, whereas in patients aged ≥ 60 years, systolic blood pressure is< 150 mmHg and diastolic blood pressure is< 90 mmHg. In patients with diabetes aged ≥ 18 years, the therapeutic target is systolic blood pressure < 140 mmHg and diastolic blood pressure < 90 mmHg.Tolerability was measured based on adverse events (AE) and adverse drug reactions (ADR) reported by patients during 1 month of candesartan therapy.

Descriptive statistical analysis was carried out to determine the general characteristics of patients. prevalence of achieving therapeutic targets, blood pressure reduction values (systolic and diastolic), MAP, and tolerability to candesartan. After that, bivariate statistical analysis was carried out to compare all variables in the two ethnic groups.All tests were two-sided, and p<0.05 was used to signify statistical significance.

RESULT:

This research begins with a pre-study that aims to find out the antihypertensives that are widely prescribed by doctors and used by the public. Data were collected from 20 pharmacies, consisting of two pharmacies in each sub-district in Kendari City, from January 2020 to March 2021. The results of the preliminary study indicated that candesartan cilexetil was included in the three antihypertensive drugs most prescribed by doctors and used in antihypertensive therapy besides amlodipine and captopril. The pre-study also showed that 78.3% of the candesartan cilexetil prescribed was generic.

Description of patient Characteristics:

Medical record data shows that there were 169 hypertension patients of Tolaki and Muna ethnicity who received candesartan cilexetil monotherapy during the study period. There were 119 patients who met the inclusion criteria, consisting of 68 people of Tolaki ethnicity and 51 people of Muna ethnicity. Fifty patients were excluded for the following reasons: 17 patients did not come for blood pressure control in the following month; 8 people were heart failure patients; 19 were post-stroke patients; and 6 patients underwent monotherapy candesartan cilexetil 16mg x 1 tablet.

The study included 112 patients (94.18%) who had just been diagnosed with high blood pressure and started candesartan cilexetil therapy (treatment naïve). Seven patients (5.82%) had been on another antihypertensive drug but their blood pressure was still too high (>140/90 mm Hg), and three patients (2.52%) were on captopril but had a cough that wouldn't go away.

Statistically, there was a significant difference in patient age between the two ethnic groups when hypertension was diagnosed (Table 1). The age of patients from the Muna ethnic group is older than that of the Tolaki ethnic group. The median age of patients of the Muna ethnicity is 57 years, with the youngest being 38 years and the oldest being 70 years, while the median age of Tolaki ethnic patients is 48 years, with the youngest being 30 years and the oldest being 70 years. There is a significant difference in the prevalence of hypertensive patients with diabetes mellitus of type 2 in both ethnic groups when diagnosed with hypertension. Muna ethnic patients who already suffer from type 2 diabetes mellitus when diagnosed with hypertension are 39.2%, while 5.9% of Tolaki ethnic patients are (Table 1).

The results of the analysis showed that there was no significant difference in the comparison of the number of patients by sex between the two ethnic groups. The mean age of patients in both groups was <60 years, and the prevalence of males was higher than females at the time of diagnosis of hypertension. The prevalences of male patients of the Muna and Toloki ethnicities are 56.90% and 57.40%, respectively. The highest level of hypertension in the two ethnic groups was hypertension in grade 2. A description of the characteristics of patients with hypertension of the Tolaki and Muna ethnicities is presented in Table 1.

Table 1: Description of the characteristics of patients with hypertension of the Tolaki and Muna ethnicities

Characteristics

Ethnic Groups

P Value

Tolaki

Muna

Age *: (years old)

Mean ± DS

Median

(minimum-maximum)

48.73 ±8.43

48.00

(30-70)

57.45 ±4.90

57.00

(38-70)

0.000

Gender ** : n (%)

Man

Women

39 (57.4%)

28 (42.6%)

29 (56.9%)

22 (43.1%)

0.597

Diabetes mellitus of type 2**: n (%)

4 (5.9%)

20 (39.2%)

0.000

Hypertension level***: n (%)

Hypertension of level1

Hypertension of level2

Hypertension of level3

Isolated systolic hypertension

26 (39.2)

39 (57.4)

3 (4.4)

9 (17.6%)

36 (70.6%)

3 (5.9%)

0.169

*Mann whitney test

**Chi Square test

***Kolmogorov-Smirnov test

Comparison of Target Achievement of Blood Pressure Therapy:

The prevalence of achieving therapeutic targets in patients from both Tolaki and Muna ethnic groups after undergoing candesartan cilexetil monotherapy for 1 month is exhibited in Table 2.

Although at the start of candesartan cilexetil monotherapy there was no significant difference in blood pressure levels between the two ethnic groups, the results of the study showed that there were significant differences in achieving blood pressure targets. This study shows that hypertensive patients from the Muna ethnic group, representing the black population, achieve fewer therapeutic targets than patients with hypertension from the Tolaki ethnic group, who represent non-black people.

Comparison of Blood Pressure Decline:

The results of this study indicate that candesartan cilexetil monotherapy for one month can reduce systolic and diastolic blood pressure in patients of the Tolaki and Muna ethnicities. The mean blood pressure for patients of Muna ethnicity before therapy was (163.73±10.40)/(94.00±9.13) mmHg, which decreased to (152.88±10.57)/(88.33±7.67)mmHg after therapy, whereas in Tolaki ethnicity the mean blood pressure decreased from (156.98±9.52)/(93.69±7.02)mmHg to (123.22±10.45)/(79.73±7.55) mmHg (Figure 1).

Figure 1: Blood pressure before and after one-month therapy of candesartan cilexetil in Tolaki and Muna ethnicities

In this study, the rate of decrease in blood pressure was the difference in blood pressure values (systolic or diastolic) before and after undergoing candesartan cilexetil monotherapy for one month. The comparative tests showed significant differences in the reduction of blood pressure (systolic and diastolic) and MAP. The median value of reducing systolic blood pressure for the Tolaki ethnic group was -33mmHg (of -10–(-60) mmHg) and -10mmHg (of 0–(-20)mmHg) for the Muna ethnic group. The decrease in diastolic blood pressure in the Tolaki ethnic group was also greater than that of the Muna ethnic group. The median values of the decrease in diastolic blood pressure are -10mmHg (of 0–(-37) mmHg) for Tolaki ethnicity and -5mmHg (of 5–(-20) mmHg) for Muna ethnicity. The median of the MAP of each ethnic group was 93.63mmHg (of 80–120mmHg) for the Tolaki ethnic group and 110mmHg (of 96.69–130.00mmHg) for the Muna ethnic group (Table 3).

Tolerability to Candesartan:

In this study, no significant difference in side effects was found between the two ethnic groups after undergoing monotherapy with candesartan 8 mg once daily for one month. The side effects complained of by some patients are dizziness, headaches, and feeling weak. These are categorized as mild to moderate side effects (Table 4).

Table 4: Comparison of side effects after undergoing monotherapy of candesartan cilexetil 8 mg one month in the Tolaki and Muna ethnic groups

Side Effects*	Ethnic Groups		*P value*
Side Effects*	Tolaki (68 individuals) n (%)	Muna (51 individuals) n (%)	*P value*
Dizziness and or headache	17 (25.0%)	6 (11.8%)	0.637
Feeling weak	1 (1.5%)	5 (9.8%)
Hyperkalemia	0	6 (11.8%)
Nothing	50 (73.5%)	34 (66.7%)

* Kolmogorov-Smirnov test.

DISCUSSION:

Age, gender, and family history are risk factors for hypertension that cannot be changed. The prevalence of essential hypertension generally increases with age. In this study, the average age of the Muna ethnic group patients was older than that of the Tolaki ethnic group patients when hypertension was diagnosed, with an average age difference of ±12 years. Some research results show that adult men aged 18–60 tend to have a higher prevalence of hypertension than women, but after age 60, the prevalence of hypertension in men becomes lower^32,33. The results of this study are similar to the results of several other studies. There is no difference in the comparison of gender proportions between the two ethnicities. In the age group of <60 years, more men suffer from hypertension than women..

Ethnicity, family history (genetics), unhealthy lifestyle, and age ≥35 years are risk factors for type 2 diabetes mellitus. People with type 2 diabetes mellitus have a greater risk of developing hypertension, caused by increased body fluid volume and resistance in peripheral blood vessels³⁴. Patients from both ethnic groups were in the age range that is a risk factor for type 2 diabetes mellitus; however, it was found that the Muna ethnic group was more have type 2 diabetes mellitus when diagnosed with hypertension. It is suspected that lifestyle, family history (genetics), or ethnicity play an important role in this.

One of the determinants of achieving the target of therapy is the selection of the right antihypertensives and doses³⁵. The results of the evaluation of the efficacy of candesartan showed that there was a statistically significant difference, although the blood pressure values at the start of therapy for the two ethnic groups were not significantly different. The prevalence of patients who achieve the therapy target according to JNC 8, as well as the average value of reduction in systolic and diastolic pressure, is higher in the Tolaki ethnic group; even the percentage of patients who have mean arterial pressure (MAP) in the normal range is also greater in the Tolaki ethnic group.This shows that the efficacy of candesartan is better (potent) in the Tolaki ethnic group.

The MAP value, together with the systolic blood pressure value and the diastolic blood pressure value, can strongly predict cardiovascular disease³⁶. The median MAP value for patients of Tolaki ethnicity is in the normal range, while that of Muna ethnicity is in the upper limit of the normal range. If this condition is accompanied by not achieving blood pressure targets (systolic and diastolic), it can increase the risk of damage to the heart, stroke, heart attack, and even the potential to become diabetes mellitus of type 2^37,38.

Several studies aimed at looking at the efficacy of candesartan in various ethnicities have been carried out. The results show that there are indeed variations in the response and efficacy of candesartan therapy in various ethnicities. A study in the United States involving 8796 black, Hispanic, and white hypertensive patients showed that the achievement of therapy targets for each ethnicity exhibited different results even though they were both undergoing ARB antihypertensive therapy. Blacks and Hispanics achieve fewer therapy targets than whites³⁹. Several other studies show that there are differences in blood pressure reduction values between the ethnic groups they studied. A study involving essential hypertension patients of Japanese ethnicity showed that candesartan could reduce blood pressure very well. Candesartan cilexetil monotherapy for 4–8 weeks can reduce systolic/diastolic blood pressure >20/10mmHg by 72%⁴⁰. According to a study by Rakugi et al.⁴¹ on people of the same ethnicity, 8mg of candesartan monotherapy for 12 weeks reduced blood pressure by -13.9/-7.8mmHg. In a study involving black American hypertensive patients, candesartan cilexetil only reduced systolic and diastolic blood pressure at week 8 by an average of -6.4/-5.1mmHg and at week 12 by an average of -9.3/-7.0mmHg⁴². The results of the research we conducted showed that the value of blood pressure reduction in the Tolaki ethnic group was similar to that of the Japanese ethnic group, while the blood pressure reduction value in the Muna ethnic group tended to be similar to that of black American ethnicity after 4 weeks of candesartan therapy.

There was similar tolerance to candesartan in patients of both ethnic groups. The prevalence of side effects did not differ significantly. In this research, patients who complain of dizziness or headaches are those who experience a decrease in systolic blood pressure >20 mmHg. In this study, six patients from the Muna ethnic group experienced hyperkalemia, and all of them were patients with hypertension who also had diabetes mellitus of type 2. Therapy using antihypertensive ARBs can increase hyperkalemia in hypertensive patients with diabetes mellitus of type 2. Hyperkalemia is characterized by an increase in serum or plasma potassium levels above normal limits, usually greater than 5.0mEq/L to 5.5mEq/L. Hyperkalemia can cause muscle weakness, paralysis, cardiac arrhythmias, and sudden cardiac death^43,44.

Several intrinsic and extrinsic factors cause people's responses to antihypertensives to vary widely. Some of these factors are race and ethnicity, age, obesity, lifestyle, and comorbidities^45,46. Judging from the research results, it is suspected that racial (genetic) factors play an important role in the response of patients in both ethnic groups to candesartan. Further investigation is needed to prove this. The limitation of this study is that the data was taken from the patient's medical records, meaning data on BMI, lifestyle, and variations in candesartan metabolizing gene polymorphisms were not obtained. It is recommended that future research use a prospective cohort method so that data on factors that influence response to drugs can be obtained and analyzed.

CONCLUSION:

There was a significant difference in the efficacy of candesartan cilexetil 8mg monotherapy for one month in hypertensive patients of the Tolaki and Muna ethnicities. The results of the study showed that the prevalence of achieving blood pressure targets and reducing systolic and diastolic blood pressure in the Tolaki ethnic group was greater than in the Muna ethnic group. There is no difference in tolerance between the two ethnic groups.

CONFLICT OF INTEREST:

The authors have no conflicts of interest regarding this investigation.

ACKNOWLEDGEMENTS:

We express our deepest gratitude to the General Directorate of Higher Education, Ministry of Education and Culture of the Republic of Indonesia, for the research funding assistance provided. We also thank the hospital staff for their warm welcome and assistance during the research.

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Received on 19.01.2023 Modified on 14.08.2023

Research J. Pharm. and Tech 2024; 17(4):1503-1509.

DOI: 10.52711/0974-360X.2024.00238

Ethnic Groups	Total of Patients n (%)	Achievements of hypertension therapeutic target				*P Value*
		Age ≥60 years		Age < 60 years or with type 2 DM
		Number of patientsn n	Patients achieving the target of therapy n (%)	Number of patientsn n	Patients achieving the target of therapy n (%)
Tolaki	68 (100%)	5	4 (5.88%)	63	60 (88.23%)	0.000
Muna	51 (100%)	16	6 (11.76%)	35	6 (11.76%)

	Ethnic Groups		P value
	Tolaki (68 individuals)	Muna (51 individuals)	P value
Decrease in systolic blood pressure *			0.000
Mean ± SD (mmHg) Median (minimum-maximum)	-33.76 ± -11.22 -33 ((-10)-(-60))	-10.35 ± -5.54 -10 (0-(-20))	0.000
Decrease in diastolic blood pressure *			0.000
Mean ± SD (mmHg) Median (minimum-maximum)	-14.67 ± -8.049 -10 (0–(-37))	-5.47 ± -7.37 -5 (5–(-20))	0.000
MAP*			0.000
Mean ± SD Median (minimum-maximum)	93.63 ± 7.24 93.33 (80 - 120)	109.93 ± 6.46 110 (96.69 - 130.00)	0.000